S100: FIRST PHASE 3 RESULTS FROM CARTITUDE-4: CILTA-CEL VERSUS STANDARD OF CARE (PVD OR DPD) IN LENALIDOMIDE-REFRACTORY MULTIPLE MYELOMA
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SUBMITTER: Einsele H
PROVIDER: S-EPMC10428371 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:IntroductionCiltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%.MethodsA cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars.ResultsTotal cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively.DiscussionThis analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.
| S-EPMC11372240 | biostudies-literature
Project description:Refractoriness to lenalidomide is an important factor determining the choice of therapy at first relapse in multiple myeloma (MM). It remains debatable if resistance to lenalidomide varies among MM refractory to standard doses vs low dose maintenance doses. In this study, we assessed the outcomes with subsequent therapies in patients with MM refractory to standard dose vs low dose lenalidomide. We retrospectively reviewed all patients with MM at our institution who received first line therapy with lenalidomide containing regimens, and assessed progression free survival (PFS) and overall survival for these patients for second line therapy, and with lenalidomide retreatment. For second line therapy, we found no difference in the PFS between standard dose refractory and low dose refractory groups (median PFS 14 months vs 14 months, p = 0.95), while the PFS for both these groups was inferior to the not refractory group (median PFS 30 months, p < 0.001 for both pairs). Similar trends were seen among these groups on lenalidomide retreatment, and on multivariable analysis. These data suggest that refractoriness to lenalidomide is not dose dependent, and definition of lenalidomide refractoriness should not depend on the dose of lenalidomide to which the disease was considered refractory.
| S-EPMC10966094 | biostudies-literature
Project description:Aim: The phase III randomized controlled trial (RCT) CARTITUDE-4 (NCT04181827) demonstrated superiority of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) over daratumumab, pomalidomide and dexamethasone (DPd) and pomalidomide, bortezomib and dexamethasone (PVd) for relapsed/refractory multiple myeloma (RRMM) patients who have received one to three prior line(s) of therapy (LOT[s]) including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide. These analyses estimate the relative efficacy between cilta-cel and other common treatment regimens, for which no direct comparative evidence is available. Materials & methods: Patient data were available from the CARTITUDE-4, CASTOR, CANDOR and APOLLO RCTs. Imbalances between cohorts on key patient characteristics were adjusted for using inverse probability of treatment weighting (IPTW). Relative efficacies were estimated with response rate ratios (RRs) and 95% confidence intervals (CIs) for overall response rate (ORR), very good partial response or better rate (≥VGPR) and complete response or better rate (≥CR), and with hazard ratios (HRs) and 95% CIs for progression-free survival (PFS). Sensitivity analyses using different analytical methods and additional covariates were explored. Results: Key characteristics were well balanced across cohorts after IPTW. Cilta-cel showed statistically significant benefit in PFS (HRs: 0.11-0.51), ≥VGPR (RRs: 1.51-5.13) and ≥CR (RRs: 2.90-35.24) versus all comparators, and statistically significant improvements in ORR over most comparator regimens (RRs: 1.22-1.90). Results were consistent across sensitivity analyses. Conclusion: Cilta-cel demonstrated benefit over other common treatment regimens, highlighting its potential to become a new standard of care option for lenalidomide-refractory RRMM patients with one to three prior LOT(s). These comparisons help to demonstrate the improved efficacy of cilta-cel in countries where the standard of care may differ from DPd/PVd.
| S-EPMC11363176 | biostudies-literature
Project description:Chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen have shown positive responses in patients with multiple myeloma (MM). The phase 2 portion of the CARTITUDE-1 study of ciltacabtagene autoleucel (cilta-cel) included a cohort of Japanese patients with relapsed/refractory MM. Following a conditioning regimen of cyclophosphamide (300 mg/m2 ) and fludarabine (30 mg/m2 ), patients received a single cilta-cel infusion at a target dose of 0.75 × 106 (range, 0.5-1.0 × 106 CAR-positive viable T cells/kg). The primary endpoint was overall response rate (ORR; defined as partial response or better) by International Myeloma Working Group criteria. A key secondary endpoint was the rate of very good partial response (VGPR) or better (defined as VGPR, complete response, stringent complete response). This first analysis was performed at 6 months after the last patient received cilta-cel. Thirteen patients underwent apheresis, nine of whom received cilta-cel infusion. Eight patients who received cilta-cel at the target dose responded, yielding an ORR of 100%. Seven of eight (87.5%) patients achieved a VGPR or better. One additional patient who received a below-target dose of cilta-cel also achieved a best response of VGPR. MRD negativity (10-5 threshold) was achieved in all six evaluable patients. Eight of nine (88.9%) patients who received cilta-cel infusion experienced a grade 3 or 4 adverse event, and eight (88.9%) patients experienced cytokine release syndrome (all grade 1 or 2). No CAR-T cell neurotoxicity was reported. A positive benefit/risk profile for cilta-cel was established for heavily pretreated Japanese patients with relapsed or refractory MM.
| S-EPMC9746030 | biostudies-literature
Project description:Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed and refractory myeloma. The most common adverse events associated with lenalidomide include fatigue, skin rash, thrombocytopenia, and neutropenia. In addition, when lenalidomide is combined with dexamethasone or other conventional cytotoxic agents, there is an increase in the incidence of venous thromboembolic events. There is now evidence that continued treatment with lenalidomide has a significant impact on survival by improving the depth and duration of response. This highlights the value of adverse event management and appropriate dose adjustments to prevent toxicity, and of allowing continued treatment until disease progression. In this review, we will discuss the different lenalidomide-based treatment regimens for patients with relapsed/refractory myeloma. This is accompanied by recommendations of how to manage and prevent adverse events associated with lenalidomide-based therapy.
| S-EPMC3430086 | biostudies-literature
Project description: Not available
| S-EPMC8079718 | biostudies-literature
Project description: Not available
| S-EPMC5004394 | biostudies-literature
Project description:Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1-21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.
| S-EPMC7685974 | biostudies-literature
Project description:This phase 1/2 trial evaluated the maximum tolerated doses, safety, and efficacy of pomalidomide, bortezomib, and dexamethasone (PVD) combination in patients with relapsed lenalidomide-refractory multiple myeloma (MM). In phase 1, dose level 1 consisted of pomalidomide (4 mg by mouth on days 1 to 21), IV or subcutaneous bortezomib (1.0 mg/m2 on days 1, 8, 15, and 22), and dexamethasone (40 mg by mouth on days 1, 8, 15, and 22) given every 28 days. Bortezomib was increased to 1.3 mg/m2 for dose level 2 and adopted in the phase 2 expansion cohort. We describe the results of 50 patients. Objective response rate was 86% (95% confidence interval [CI], 73-94) among all evaluable patients (stringent complete response, 12%; complete response, 10%; very good partial response, 28%; and partial response, 36%) and 100% among high-risk patients. Within a median follow-up of 42 months, 20% remain progression free, 66% are alive, and 4% remain on treatment. Median progression-free survival was 13.7 months (95% CI, 9.6-17.7). The most common toxicities were neutropenia (96%), leukopenia (84%), thrombocytopenia (82%), anemia (74%), and fatigue (72%); however, the majority of these were grade 1 or 2. The most common grade ≥3 toxicities included neutropenia (70%), leukopenia (36%), and lymphopenia (20%). Deep vein thrombosis occurred in 5 patients. In conclusion, PVD is a highly effective combination in lenalidomide-refractory MM patients. Weekly administration of bortezomib enhanced tolerability and convenience. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy. This trial was registered at www.clinicaltrials.gov as #NCT01212952.
| S-EPMC5606008 | biostudies-literature
Project description:This phase 2 trial investigated reinduction with carfilzomib, pomalidomide, and dexamethasone (KPd) and continuous pomalidomide/dexamethasone in patients at first progression during lenalidomide maintenance. The second objective was to evaluate high-dose melphalan with autologous stem cell transplantation (HDM/ASCT) at first progression. Patients were eligible who had progressive disease according to International Myeloma Working Group (IMWG) criteria. Treatment consisted of 8 cycles carfilzomib (20/36 mg/m2), pomalidomide (4 mg) and dexamethasone. Patients without prior transplant received HDM/ASCT. Pomalidomide 4 mg w/o dexamethasone was given until progression. One hundred twelve patients were registered of whom 86 (77%) completed 8 cycles of KPd. Thirty-five (85%) eligible patients received HDM/ASCT. The median time to discontinuation of pomalidomide w/o dexamethasone was 17 months. Best response was 37% ≥ complete response, 75% ≥ very good partial response, 92% ≥ partial response, respectively. At a follow-up of 40 months median PFS was 26 and 32 months for patients who received KPd plus HDM/ASCT and 17 months for patients on KPd (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.37-1.00, P = 0.051). PFS was better after longer duration of prior lenalidomide (HR 3.56, 95% CI 1.42-8.96, P = 0.035). Median overall survival (OS) was 67 months. KPd-emerging grade 3 and 4 adverse events included hematologic (41%), cardiovascular (6%), respiratory (3%), infections (17%), and neuropathy (2%). KPd followed by continuous pomalidomide is an effective and safe triple drug regimen in second-line for patients previously exposed to bortezomib and/or refractory to lenalidomide.
| S-EPMC9529060 | biostudies-literature